It has become increasingly clear that low oxygen levels (hypoxia) contribute to the pathogenesis of nearly all human blindness disorders, especially those with a component of neovascularization. Hypoxia, via the Hypoxia Inducible Factors (HIFs), regulates several pathways known to promote neovascular disease, however, the exact role of the HIFs in this process remains unclear. Accordingly the long-term objective of this project is to demonstrate a role for the HIF pathway in pathological angiogenesis of the retina and to identify how it interacts with signaling pathways involved in retinal disease with the aim of identifying new therapeutic strategies for human blindness disorders. Based on this, three specific aims will be pursued: specific Aim 1 will define a role for HIF-11 in ocular neovascularization and assess the relative contribution of the hypoxic response in the neural retina and endothelial cells to pathological retinal angiogenesis. Specific Aim 2 will evaluate whether hypoxia regulates two developmental signaling pathways (Wnt and Notch) in the context of retinal neovascular disease. Specific Aim 3 will examine the molecular mechanisms by which the HIF pathway regulates Wnt and Notch in the endothelium and apply these findings to a mouse model of pathological retinal angiogenesis. To achieve these goals, I will combine various methods of cell biology, immunohistochemistry, genetics, cell culture, and animal modeling to investigate how hypoxia promotes pathological retinal angiogenesis. The rationale of the proposed research is that understanding the molecular mechanisms responsible for promoting ocular neovascularization will lead to improved therapeutic targets and treatment strategies for diseases such as Age-related Macular Degeneration (AMD) and diabetic retinopathy (DR). Furthermore, since the retina is part of the CNS, these studies may be applicable to other diseases, including brain cancers. PUBLIC HEALTH RELEVANCE: AMD is one of the most common human blindness disorders in the US, affecting approximately 1.5% of the population over 40. Despite recent advances in anti-angiogenic treatments for AMD, current therapies generally yield modest results or are completely ineffective in a large number of patients, up to 40%. This demonstrates that improved understanding of the mechanisms underlying pathological retinal angiogenesis is needed, and that these studies may lead to improved therapeutic strategies. This study is of great significance to public health because it aims to do these things. )